Endothelial Injury and Development of Coronary Intimal Thickening After Heart Transplantation

Sponsor

Gladwin, Mark, MD (Other)

Overall Status

Terminated

CT.gov ID

NCT01848301

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Coronary allograft vasculopathy (CAV) is the leading cause of late graft failure and second leading cause of late mortality after heart transplantation. CAV has been associated with a variety of traditional risk factors for atherosclerosis; however, immune mediated injury from development of de-novo donor-specific antibodies after transplantation also likely plays an important role. Similar to the progression of traditional atherosclerosis, it is likely that endothelial dysfunction is the precursor to the development of intimal thickening and CAV.

The investigators hypothesize that coronary allograft vasculopathy after heart transplantation as defined by progressive neointimal hyperplasia is preceded by endothelial dysfunction, which in turn is at least partly mediated by donor specific antibodies.

The investigators are proposing a prospective study in humans to test the above hypothesis and further mechanistically understand how CAV progresses. In this study the investigators will test for coronary endothelial function by infusing acetylcholine into the coronary artery and measure intimal hyperplasia by optical coherence tomography (OCT) and compare findings in patients with and without donor specific antibodies.

Condition or Disease	Intervention/Treatment	Phase
Cardiac Allograft Vasculopathy Antibody Mediated Rejection	Device: Optical Coherence Tomography Drug: Acetylcholine Procedure: Brachial Artery Flow Mediated Dilation	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

Endothelial Injury and Development of Coronary Intimal Thickening After Heart Transplantation

Study Start Date :

Sep 1, 2012

Actual Primary Completion Date :

Sep 1, 2014

Actual Study Completion Date :

May 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single arm All subjects will undergo a Brachial Artery Flow Medicated Dilation prior to heart catheterization. After routine heart catheterization, images of their coronary artery will be recorded by Optical Coherence Tomography (OCT) during infusion of Acetylcholine.	Device: Optical Coherence Tomography OCT imaging of the LAD coronary artery Other Names: OCT Drug: Acetylcholine Infusion in the coronary artery to study endothelial function Other Names: Miochol Miochol-e Procedure: Brachial Artery Flow Mediated Dilation Assess peripheral brachial artery endothelial function

Arm

Intervention/Treatment

Experimental: Single arm

All subjects will undergo a Brachial Artery Flow Medicated Dilation prior to heart catheterization. After routine heart catheterization, images of their coronary artery will be recorded by Optical Coherence Tomography (OCT) during infusion of Acetylcholine.

Device: Optical Coherence Tomography

OCT imaging of the LAD coronary artery

Other Names:

OCT

Drug: Acetylcholine

Infusion in the coronary artery to study endothelial function

Other Names:

Miochol

Miochol-e

Procedure: Brachial Artery Flow Mediated Dilation

Assess peripheral brachial artery endothelial function

Outcome Measures

Primary Outcome Measures

The primary endpoint will be a comparison of intimal thickness in the coronary artery by Optical Coherence Tomography with presence or absence of donor specific antibodies. [baseline (year 1 post transplant) and annually for 2 years]

Secondary Outcome Measures

Assessment of epicardial coronary endothelial function by measuring change in vessel size in response to acetylcholine and how this compares to peripheral endothelial function. [baseline (year 1 post transplant) and annually for 2 years]
Prospectively determine the association of HLA and non-HLA donor specific antibodies that activate complement with endothelial dysfunction and intimal thickening. [baseline (year 1 post transplant) and annually for 2 years]
Gene expression of white blood cells by microRNA and how this relates to endothelial function and intimal thickness. [baseline (year 1 post transplant) and annually for 2 years]
Plaque characterization in coronary artery by OCT [baseline (year 1 post transplant) and annually for 2 years]
Natural progression of coronary allograft vasculopathy over first 2 years after transplantation [baseline (year 1 post transplant) and annually for 2 years]
Comparison of endothelial function in the coronary artery with presence or absence of donor specific antibodies. [baseline (year 1 post transplant) and annually for 2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subjects who are 1 year post heart transplantation
Subjects will include both male and females
Be at least 18 years of age

Exclusion Criteria:

Known coronary artery disease after transplantation
Evidence of strong or moderate antibodies already present at the time of the transplant
Severe renal dysfunction defined as creatinine clearance of <30 or on hemodialysis.
3 or more episodes of acute cellular rejection
Females who are pregnant
Patients requiring endomyocardial biopsy at the time of catheterization
Patients unable to tolerate heparin or systemic anticoagulation
History of multi-organ transplant
Patients unable to give consent